The prevalence of obesity with its associated co-morbidities is rapidly reaching epidemic proportions. Males and females maintain distinctive fat distribution patterns. Males tend to accumulate more visceral fat whereas females have more subcutaneous fat. The phenomenon of maintaining typical fat distributions suggests sex-specific mechanisms of body fat regulation. While females decrease energy expenditure to conserve energy during caloric restriction or after fat removal, males exhibit hyperphagia to restore fat. Our lab has found that syndecan-3-deficient mice resist diet-induced obesity and show improved glucose tolerance, the result of decreased caloric intake in males whereas increased energy expenditure in females. Mice with targeted disruption of the gene encoding granulocyte macrophage-colony stimulating factor gain fat. Males show increased caloric intake while females show reduced energy expenditure. These data suggest that males and females use distinct strategies to regulate energy balance. The overall goal for this proposal is to test specific hypotheses about the mechanistic differences between males and females that result in different body-fat accumulation and different strategies by which that body fat is defended. [unreadable] [unreadable] [unreadable]